chapter one metal-directed macrocyclization reactions ... · work involving condensations using...
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1
Chapter One
Metal-Directed Macrocyclization Reactions
Involving Formaldehyde, Amines and Mono- or Bi-
Functional Methylene Compounds
1. Introduction
The synthesis of large saturated organic rings incorporating a number of
heteroatoms presents a challenge for synthetic chemists which has been
approached in a number of ways. A number of routes to macrocyclic molecules
have been developed employing standard organic chemistry approaches1. In all
reactions, an important step must be the cyclization process, but this is not
entropically favoured when forming large rings, and consequently reactions
may occur in low yield or, in order to promote higher yields, must be
accomplished under high dilution conditions where the cyclization is more
favoured. Nevertheless, some macrocycles can be prepared conveniently in
reasonable yields by direct organic routes.
However, it has been recognised for several decades now that it is possible to
make use of the 'organising' capacity of metal ions to promote reactions which
lead to macrocyclization2. One consequence of binding some reaction
components to a metal ion is that co-ordination reduces the large-ring
reactions occurring in 'pure' organic routes to small-ring reactions where the
building of small (typically six-membered) rings incorporating the metal ion is
2
then important. Formation of the small chelate rings is favoured entropically,
in the same way that small-ring formation reactions in organic chemistry are
also facile. There are a number of ways in which metal-directed reactions can
occur, but dominantly they involve the reaction of two heteroatoms bound in
adjacent sites in the co-ordination sphere of a metal ion with other reagents
which lead to formation of a new chain linking the originally separate
heteroatoms. Where a sufficient number of these reactions occur around a
metal ion, a macrocyclic molecule ligated to the metal ion can result;
alternatively, a larger polydentate but not cyclic molecule can result if reaction
is limited in some way.
Metal-directed reactions leading to macrocyclic molecules are reasonably
diverse, and it is the intention of this review to devote itself largely to
reactions which produce saturated macrocyclic ligands and related polydentate
molecules and involve formaldehyde as a reagent. Moreover, incorporation of
additional reagents in the reaction generates alternate products. Where
monofunctional or bifunctional methylene compounds of sufficient acidity are
involved in addition to formaldehyde, these carbon acids may be incorporated
into new rings along with formaldehyde, generating macromonocycles which
contain additional pendant groups which may carry potential donor groups.
These pendant donor groups increase the capacity of ligands to saturate the
coordination sphere of metal ions, and add an additional 'dimensionality' to the
macrocycle as a result of their spatial orientation relative to the donors in the
macrocycle.
3
1.2 Reactions Involving Formaldehyde Alone
Coordinated primary amines present the most appropriate sites for reaction
with formaldehyde via reaction as in eq. (1).
R-NH2 + CH2O R-N=CH2 + H2O R-NH-CH2-OH (1)
where the imine an the aminol may exist in equilibrium. Although coordinated
imines are more stable than free imines, and have been isolated and
characterised in some circumstances3, they remain susceptible to further
nucleophillic attack. Where no other added nucleophile is available, further
reaction with accessible components of the precursor complex, such as an
additional primary amine, may occur. Reactions between coordinated
molecules and formaldehyde alone have received only modest attention
compared to some other metal directed reactions. However, they represent a
useful starting point for this review, and are addressed below.
One of the earliest reactions involving a polyamine coordinated to a metal ion
and formaldehyde was reported by Alcock et al.4. The cyclization involved the
reaction of a tetrahyrdrofuran solution of L1 with formaldehyde and nickel(II)
salts in air to give the macrocyclic nickel(II) complex of L2. Condensation of
one formaldehyde molecule with one primary amine has been followed by
nuclelophilic attack on the resultant imine (or aminol) by the adjacent primary
amine, the intramolecular reaction generating a new chelate ring and
4
completing cyclization. A similar condensation was reported for co-ordinated
dihydrazines by Peng et al.5
Steric strain in complexes of ligands such as L2 is not marked, as six-
membered chelate rings form. However, it has been observed that adjacent
coordinated amines can be linked directly in the same manner. Geue et al.6
have shown that cis-disposed amines may react with formaldehyde to form
diaminmethylene (>N-CH2-N<) links in several cobalt(III) polyamine
compounds resulting in 4-membered chelate rings. Despite the strain present
in the small chelate rings, formation reactions are surprisingly facile.
A reaction which produced a macrocyclic ether complex with a coordinated
oxygen around a copper(II) template has been reported7 . This was achieved by
the addition of formaldehyde to a reaction mixture of 4,7-diazadecane-1,10-
diamine, 2-aminoethanol and copper(II). Four intramolecular condensations
occur leading to four new links identified in bold in L3. Apart from >N-CH2-N<
5
formation, attack of the ethanolamine oxygen on an aminol has produced an
ether via a new -O-CH2-N< bridge.
A range of interesting reinforced hexaaza macrocycles with two additional
ethylene bridges joining adjacent nitrogens (L4, L5, L6, L7) were synthesised
by Suh and co-workers8,9,10. These were produced by reacting
polyaminoalkanes (see eua. (2)-(5) below) with formaldehyde, using nickel(II)
as a template, with the variation that both ethane-1,2-diamine and a
tetramine were present in the later two synthesis. It is notable that all
reactions produce a 14-membered basic macrocycle framework, a ring size
which is generally the most thermodynamically stable in complexes with first
row transition metal ions. Again, in L4-L7, new links completing the
macrocycles are shown in bold. The similarity to the synthesis forming L3,
where again a 14-membered basic ring is formed, are obvious.
6
Ni + [Ni(4)]2 2 2
Ni + [Ni(5)]
Ni + [Ni(6)]
Ni + [Ni(7)]
2+
2+
2+
2+
2+
2+
2+
2+
H N NH NH CH O+
2 2H N NH NH + 2CH O
2H N NH NH 2
NH +2CH O 2
H N2
NH+
2H N NH NH
2NH +
2CH O
(2)
(3)
(4)
(5)2H N2
NH+
Alternative condensation reactions involving two formaldehyde molecules in
concert are known. Also in the early seventies Brush et al.11 found that bis((S)-
serinato)copper(II) L8 reacted with excess formaldehyde at pH 7-9 to form the
complex L9. In the absence of the metal ion no reaction was found to take
place. Presumably, acidity of the amino acid methylene in the coordinated
complex is sufficiently high to act as a nucleophile along with the alcohol arm.
Three formaldehyde molecules are incorporated in each amino acid unit, as
indicated in bold in the drawing of L9.
7
The condensation of formaldehyde with glycinatobis(ethylenediamine)-
cobalt(III) to yield [(-hydroxymethylserine)bis(ethylenediamine) cobalt(III)]2+
L10 and the macrocyclic species [(-hydroxymethylserine) (1,4,8,11-tetraaza-
6,13-dioxacyclotetradecane) cobalt(III)]2+ L11 was the first reported
condensation of this type around a octahedral metal ion12. In the latter
compound, apart from attack of a formaldehyde on the glycine, new chelate
rings containing an ether oxygen are formed by attack of the oxygen of one
aminol on an adjacent imine carbon, both arising initially from primary amine
and formaldehyde condensation.
8
A range of macrocyclic oxatetraazacycloalkanes copper(II) complexes (L12,
L13, L14, L15) have been produced in which the oxygen, while still a member
of the macrocyclic ring, was not coordinated to the metal ion13. They were
produced by the condensation of two formaldehyde molecules with two cis-
disposed amines in the copper(II) complexes of the precursor
polyaminoalkanes, as in L11 above. New links formed are shown in bold in L12
L15. The procedure was only found to be effacious when the final product
was essentially a 14- or 15-membered macrocycle; attempts to perform the
equivalent chemistry to produce 13- or 16-membered macrocycle were
unsuccessful.
1.3 Reactions Involving Formaldehyde and Ammonia
A coordinated imine is highly activated towards nucleophilic attack, and we
have seen in the previous section how an adjacent coordinated amine can act
as an efficient nucleophile. It is hardly surprising, therefore, to find ammonia
itself, as well as uncoordinated primary amines, can participate in reactions in
concert with formaldehyde and coordinated amines. In effect, ammonia
9
functions as an acid in these reactions, releasing a proton and permitting the
amide ion to attack the imine, as in eq. (6), where coordination of the imine
nitrogen is implied.
R-N=CH[Co(L17)]3+ [Co(L17)]3+ + -NH2 + H+ R-NH-CH2-NH2 (6)
The primary amine terminating the new chain still carries two protons, and in
principle can undergo two additional similar reactions until converted to a
tertiary nitrogen. This capacity to act as a nucleophile in three successive
reactions was first utilised in reactions to form macrobicyclic polyamines,
members of the cryptate family of encapsulating molecules.
Ligands that effectively encapsulate metal ions have received a great deal of
attention since the early seventies and an important class of these ligand are
the cryptates. Sargeson and co-workers have used formaldehyde in concert
with other reagents as and important synthetic reagent to produce a range of
cryptates of varying structures, physical and chemical properties, employing
inert complexes as precursors.
One of the earlier of these ligands produced was the macrobicyclic octaaza
cobalt(III) complex of sepulcrhate14 L16. This was produced by mixing
[Co(en)3]3+, ammonia and formaldehyde in aqueous solution kept strongly
basic using Li2CO3. The equivalent chemistry was also carried out on the
[Co(sen)]3+ complex (sen=L17) to produce the heptaaza [Co(L18)]3+ 15 and on
10
the [Co(L19)]3+ complex 16 to produce heptaaza [Co(L20)]3+ . In the latter two
cases, one side of the molecule is already 'capped' with a saturated carbon
framework, making them unavailable for facile aminol or imine formation.
Condensation of the formaldehyde molecules with three primary amines on an
octahedral face produces three imines (or aminols) disposed in such a manner
that they can readily undergo reaction with an ammonia molecule which
effectively 'caps' the face by formation of three -NH-CH2-N< links. Although
this is presumably a stepwise and not concerted process, in the presence of
excess formaldehyde and ammonia the reaction proceeds to completion in high
yield under mild conditions. In all of the above complexes, the new aza caps
formed by the condensations do not involve coordination of the 'cap' nitrogen to
the metal ion as the lone pair of the nitrogen is exo to the cavity.
The analogous chemistry to that reported with sen was also achieved with the
N3S3 donor set ligand 'ten' L21 in which the thioether donors play no part. This
produces the macrobicyclic complex of azacapten L2217.
11
Similar chemistry can be promoted around labile metal ions, although little
work involving condensations using formaldehyde and ammonia alone has
been reported. Suh et al.18 have produced an interesting hexaazaalkane L23 by
reacting formaldehyde, ammonia and ethane-1,2-diamine in the presence of
nickel(II). Also produced in this reaction is the hexadentate tripodal heptaaza
ligand L2419,20 which can be seen to be the half-capped analogue of L16
mentioned earlier. However, when heated with excess formaldehyde and
ammonia in dimethyl sulfoxide it readily converts to its square planar co-
product [Ni(L23)]2+, rather than producing the macrobicycle in any significant
yield.
Bernhardt et al.21 have also described the orange complex [Ni(L23)]2+ formed
by reacting [Ni(en)3]2+ (en = ethane-1,2-diamine) with ammonia and
12
formaldehyde solution at room temperature, together with another yellow
square planar product [Ni(L25)]2+. They also found that the equivalent
chemistry can be performed using copper(II) as a template, producing the
additional species [Cu(L26)]2+. The high-field ligands generated in these
reactions promote square-planar geometry for Ni(II) rather than octahedral,
driving the conversion of L24 to L23 reported above, whereas Cu(II) has a
strong inherent preference for square planar geometry. The facility of the
formation of these methylene links to an ammonia ion are shown by the ready
formation of molecules such as L25 and L26.
In place of ammonia, unbound amines can participate in condensation
reactions, although few examples of this type have appeared. One pendant
macrocycle of this type was reported by Suh et al.22. They synthesised the
nickel(II) complex of the ligand L27 by reacting formaldehyde and
methylamine in the presence of the nickel(II) complex of L23. Here a pendant
methyl group is attached to the apical nitrogen in the new 6-membered chelate
ring of the product, with the two protons of the methyl amine replaced in
reaction with two adjacent imines.
13
More recently Suh et al.23 have extended this chamistry by replacing ammonia
with ethanolamine and using Au(III) as a template produce the potentially
sexidentate ligand L28.
In similar reactions, Rosokha et al.24 have reported the condensation of the
nickel(II) complex of 3,7-diazanonan-1,9-diamine with formaldehyde and
aliphatic diamines to produce bis(pentaazamacrocyclic) complexes which
consist of two 14-membered macrocycles joined by an aliphatic bridge between
the non coordinating nitrogen of the new chelate rings L29.
14
1.4 Reaction Involving Formaldehyde and Monofunctional
Methylene Compounds
To date, essentially all reactions in this category have involved the
nitroalkanes [R-CH2-NO2], since these molecules exhibit sufficient acidity in
the methylene adjacent to the nitro group to act, in basic solution, as efficient
nucleophiles for reaction with imines generated from formaldehyde
condensation with coordinated amines. The reaction proceeds as defined in eq.
(7), where coordination of the imine nitrogen to a metal ion during the reaction
is implied.
R-N=CH2 + -CH(R)-NO2 R-NH-CH2-CH(R)-NO2 (7)
The arm generated in this reaction is still an efficient carbon acid, and can
participate in further condensation reactions, at one site if R = alkyl or aryl
group, and at two sites if R= H. Consequences of these addition reactions
where they are internalised in the same molecule are discussed below.
15
1.4.1 Nitromethane
Sargeson and co-workers have expanded their work with cryptates by using
nitromethane as an alternative to ammonia as a nucleophile in the
condensation with formaldehyde. This still allows condensation with three
facially-disposed amines and three formaldehyde molecules, but results in the
apical atom being a carbon with an attached pendant nitro group rather than a
tertiary nitrogen. The pendant nitro group can then be easily reduced to a
primary amine providing a site for additional chemistry, and an additional
potential coordination site.
The reaction between [Co(en)3]3+, formaldehyde and nitromethane in aqueous,
basic solution produced the cobalt(III) complex of the macrobicyclic hexamine
diNOsar L3025 in good yield, analogous to the synthesis of the sepulchrate
([Co(L16)]3+). The ligand is formed in a stepwise process via the condensation
of three formaldehyde units and one nitromethane at each end of the molecule
via formation of imine intermediates. Also produced in low yield (~2%) by the
reaction was the cobalt(III) complex of the half capped analogue NOsen L31 in
which only one end of the molecule is capped, giving some indication of the
probable stepwise nature of the reaction.
Once again, the reaction has been repeated with a large number of analogous
complexes in which one end of the molecule was unavailable for capping,
usually with cobalt(III) acting as a template. These included the capping of the
cobalt complexes of sen L17,26 ten L2527 and taetacn L1928 to produce the
cobalt(III) complexes of L32, L33 and L34. The chemistry has also been
16
described with analogous octahedral complexes of inert metal ions such as
Rh(III), Ir(III) and Pt(IV).29, 30
In an attempt to produce a more rigid cryptand Geue et al.31 substituted
trans-cyclohexane-1,2-diamine for ethane-1,2-diamine in the precursor
cobalt(III) complex. This produced the complex of L34 and the monocapped
analogue [Co(L36)]3+. The reaction was found not to proceed as easily as that
using [Co(en)3]3+ as starting material, and at equivalent temperatures only the
monocapped species was produced in reasonable yield. To produce reasonable
yields of the dicapped species it was necessary to use higher temperatures.
17
In a reversal of the norm, Gainsford et al.32 carried out a synthesis on what
could be conceptualised as a cryptand with the sides removed. They reacted
[Co(tame)2]3+ L37 with formaldehyde and nitromethane to produce the highly
constrained macrotricyclic complex L38 in reasonable yield (ca. 50%). The
ligand has been formed by three formaldehyde and one nitromethane molecule
condensing to form a trigonal cap on one side of the complex, and two
formaldehyde units condensing on the other side of the molecule to form two
four-membered chelate rings fused at a tertiary nitrogen. Two other products
L39 and L40 were found in minor yield (10%). In both, a trigonal cap still
occupies one side of the molecule; however on the other side only one
methylene bridge remains. The other has been replaced by a six member
chelate ring with a pendant nitro group on the ring carbon opposite to the
metal. This has been formed by the condensation of two formaldehyde units
and one nitromethane, and varies in the two molecules in its mode of
attachment. In the former, both methylenes are attached to amines of the
same 'tame' molecule while in the later there is one methylene attached to
each 'tame' molecule.
18
Further work on the same reaction by Geue et al.33 found the additional
product L41, which is essentially similar to the complex L38, but with an
additional fused 4-membered chelate ring.
A variation on this theme was the use of [Co(tach)2]3+ L42 in a condensation
reaction by Geue et al34. The product, L43, shows the formation of a trigonal
cap composed of three formaldehyde units and one nitromethane on one
19
octahedral face, as occurred in the reactions using 'tame'. However, on another
face the capping process has been intercepted to form a stable carbanion
chelate and to methylate the remaining tridentate amine. The maintenance of
this deprotonated form (retained in acid solution) may be due to delocalisation
and the strain engendered in chelating the relatively rigid cage to the metal
ion.
One of the only condensations around a labile metal ion using nitromethane
reacted the copper(II) complex of 4,7-diazadecane-1,10-diamine with
nitromethane and formaldehyde in methanol to produce the 15-membered
macrocycle L44.35 The alcohol pendant is probably the result of an immediate
reaction between a formaldehyde molecule and the acidic proton at the site
formed following condensation of two formaldehyde units and one
nitromethane. Whereas all the acidic protons of nitromethane are replaced by
reaction on a trigonal face, reaction in a plane with only two amines requires
only two acidic protons to be employed. In the presence of excess formaldehyde,
the -NH-CH2-CH(NO2)-CH2-NH- bridge readily undergoes additional reactions
at the central carbon. For reactions directed in one plane, i.e. around metal
20
ions preferring square planar geometry, only molecules of the type R-CH2-NO2
are required, as addressed below.
1.4.2 Nitroethane
Reactions similar to those above around labile metal ions such as Cu(II) and
Ni(II) do not yield macrobicycles in any measurable yields. However, it has
been found that facile high yielding syntheses of monomacrocycles are
possible. One of the most carefully examined series of reactions has involved
use of formaldehyde and nitroethane. This latter reagent may condense with
two formaldehyde residues and two cis-disposed amines (via the imine
intermediate) in the presence of base to form a six membered chelate ring with
pendant nitro and methyl groups attached to the central carbon atom opposite
the metal in the chelate ring. This cyclization has been used extensively to
synthesise a range of cyclic and acyclic polyamine ligands, especially using
copper(II) as a template. As with nitromethane, the nitro pendant group may
be easily reduced to an amine which, after the replacement of the original
21
square planar template with a metal ion preferring octahedral geometry, may
be used as a ligating arm to encapsulate the metal ion.
A good example of a ligand capable of this, and also one of the first examples of
this type of ligand produced using nitroethane and formaldehyde was
synthesised around a [Cu(en)2]2+ template.36 The macrocyclic ligands L45 and
L46 and the half capped analogue L47 were produced around the copper(II)
template in the presence of base (triethylamine) in methanol. It was also found
that, by carefully controlling the ratio of reagents and the rate of addition of
formaldehyde, it is possible to produce almost exclusively either the
macrocyclic or half-capped species. The species L45 and L47 can be viewed as
'planar' analogues of L30 and L31 which form on the trigonal face of an inert
octahedral complex, the former being directed by the preferred square planar
geometry of the metal ion and the choice of carbon acid.
In the synthesis of the macrocycle two generic isomers are possible, with the
methyl (and nitro) groups in syn L46 or anti L45 dispositions. The majority
(~80%) has anti geometry. As the hydrochloride salt of the free hexamine
ligand obtained following zinc reduction, this anti form is markedly less
soluble, allowing the two to be separated. The stereoselectivity towards the
anti form is thought to be due in part to a weak axial interaction between the
22
copper ion and one of the nitro groups during formation directing the
chemistry preferentially toward the anti isomer.
The equivalent chemistry has been extended to the copper(II) complexes of a
range of tetraazaalkanes to produce 13-,14-,15- and 16- membered macrocycles
and a strapped 15-membered macrocycle (L4837, L4938,L5039, L5140, L5241).
Interestingly, unlike the ether analogues produced using formaldehyde alone
(L12-L15) the 13- and 16- membered macrocycles form easily in good yield,
showing the efficacy of the synthetic procedure. There is little variation in the
yield for the reaction with varying ring size; however, the synthesis of the 14-
and 15-membered species proceeds noticeably more easily than the other
reactions, suggesting that the thermodynamic stability of the product is of
importance to the success of these reactions. Following a route similar to that
used to produce L52, Hancock and co-workers have produced analogous
reinforced macrocycles with different sized cyclic systems42,43(L53, L54).
23
The procedure was also applied to the (RR,RR)- [or (SS,SS)-] and (RR,SS)-
[Cu(chxn)2]2+ complex (chxn = trans-cyclohexane-1,2-diamine) to produce the
cyclam analogue L55 and the half capped species L56. Interestingly, the
various chiral forms of the precursor complex tend to produce different ratios
of the cyclic and acyclic forms. This has been attributed to spatial constraints
enforced on the amines by the various isomers44, since the central carbon atom
of the new six-membered chelate ring is a pseudoasymmetric centre in the
(RR,SS)-isomer, and disposition of the coordinated chxn residues varies with
the chirality in the residues and of this centre. In a manner analogous to L45,
the cis isomer of L55 with nitro groups disposed on the same side of the
macrocyclic plane has also been isolated in proportions similar to that found
for the L45, L46 system.45 The closely related asymmetric complex L57 has
also been produced by beginning with a coper complex containing one ethane
diamine unit and one 2,3 diaminocyclohexane unit.45
The same procedure has been applied to a number of copper(II) complexes
with other donors in addition to a pair of cis-disposed amines to produce a
24
range of corresponding cyclic and acyclic species (L5846, L5947, L6048,
L6149,L6245). It is interesting to note that L61 is the result of a two step
synthesis in which the immediate precursor is the acyclic complex of L23,
formed first by the reaction of formaldehyde and ammonia on [Cu(en)2]2+ , as
described above.
While the majority of the complexes produced using formaldehyde and labile
metal templates have been mononuclear, some binuclear species templated by
copper(II), nickel(II) and palladium(II) metal ions have been produced. The
first synthesis was performed by condensation of bis(1,5-diaminopentan-3-
ol)dicopper(II) ion L6350 with formaldehyde and nitromethane in basic
methanol to produce the binucleating macromonocyclic complex L64. A similar
reaction was carried out on the bis(1,5-diaminopentan-3-thilato)dinickel(II) ion
L65 which is analogous to L63, but with the O- donors replaced by sulfur
atoms. The result was a similar binuclear complex L6651, except that the
former reaction yielded L64 as the anti isomer, whereas the latter reaction
yielded L66 as the syn isomer. Although it was not clear that the isomers were
formed stereospecifically, they were formed dominantly. Why the specificity is
directed differently in each case is not clear, although the product L66 adopts a
25
'butterfly' geometry with both Ni(II) centres 'hinged' through the S atoms, and
the -NO2 groups are weakly coordinated in axial sites. Distortion towards this
symmetry in the precusor may drive the outcome. In contrast, L64 has both
Cu(II) centres and all donors in a common plane. The nickel(II) chemistry
above is reproduced with palladium(II) as the templating metal.52
Recently, palladium(II) has also been shown to be an efficient template for
some of the related mononuclear reactions described above.53 Pd(II) forms
much stronger complexes than the labile Cu(II) ion that do not tend to
decompose under the basic conditions employed in these reactions. This has
allowed the synthesis of a number of ‘swollen’ macrocycles (16 and 18
membered macrocycles) which have proven to be difficult to produce using the
more conventional copper or nickel templates (L67, L68, L69).
26
Interestingly the stereo selectivity of the reactions seems greater with the
Pd(II) template with L67 forming almost solely as the trans isomer depicted.
This is in contrast with the same ligand (L45) produced around a Cu(II)
template where appreciable amounts of the cis form (L46) were formed. For
the 16 and 18 membered macrocycles (L68 and L69) there is an apparent
reversal with only the cis forms and isolated. The chemistry has also been
extended to Au(III) and Re(III) ions. The gold template forms an analogue of
L46 and the half capped L47, however with both carrying a stable negative
charge on one of the secondary amines.54 When the equivalent chemistry is
attempted around rhenium the metal is ejected from the complex and the
heterocycle 1,4-bis(2’-nitropropanyl)-6-methyl-6-nitro-1,4-diazacycloheptane
(L70) is formed.54
27
The copper(II) complexes of the potentially binucleating ligands L71 and L7255
were treated with formaldehyde and nitroethane in basic aqueous media to
produce the macrobicyclic species L73 and L74. In the case of L71, the
monocapped macrocycle L75 was also isolated. The substituted spiro-bicyclam
ligands L73 and L74 require the two macrocyclic planes to lie approximately
90o to each other, as the central spiro carbon of the molecules is a tetrahedral
centre, the ligands being fully saturated.
28
1.4.3 Other Nitroalkanes
Reaction of a range of nitro substituted molecules of form R-CH2-NO2 (where
R is an alkyl or substituted alkyl group), formaldehyde and base with the
copper(II) and nickel(II) complexes of 4,7-diazadecane-1,10-diamine and 3,6-
diazaoctane-1,8-diamine respectively produced a range of 13- and 14-
membered macrocyclic products (L76 and L77) with one nitro pendant and the
R group remaining as the other pendant. This chemistry is largely unaffected
by choice of R group.
Evidence of this is also given by replacing nitroethane with nitroproane in the
reaction with bisethanediamine copper(II) to produce the analogues of L45 and
L46, L7856 and L79.57 The inclusion of a carbon acid which produces a longer
alkyl pendant has little effect on the ratios of the two isomers produced in the
reaction.
29
1.4.4 Other Monofunctional Reagents
Considering the efficacy of formaldehyde as a reagent in concert with
ammonia, amines and strong carbon acids such as nitroalkanes, it is hardly
surprising that a deal of attention has been paid to possible alternate reagents
that may be used in concert with formaldehyde to produce new species.
Reactions involving formaldehyde and other reagents in organic chemistry are
extensive; however, metal template reactions which involved species similar to
those discussed above are more limited.
Attention has been focussed recently on modifying the caps of the cryptand
species. This is done either to change the actual physical properties of the cage
or to allow further organic chemistry to be carried out at the cap (e.g. to attach
it to larger molecules). Many of the reaction do not involve chemistry of the
type under discussion, but there are some relevant exceptions. One such
reaction has been reported by Daszkiewicz et al.58. They have shown that a
cobalt(III) complex of the pyruvate imine L80 is an effective nucleophile in
condensing with formaldehyde and [Co(sen)]3+, resulting in a functionalised
sarcophagine cage L81. Here, the methyl group of the pyrvate imine is
sufficiently acidic to act as a tribasic carbon acid, analogous to the chemistry
described for nitromethane earlier. The product L81 may readily be reduced
30
and then reoxidised to form a pendant amino acid L82 from which a range of
organic chemistry may proceed.
Another method of adding functionality to the cap of cryptands has been
described by Hohn et al.59. They report the synthesis of cryptand-like
molecules from the imine derivatives of [Co(sen)]3+ (formed through the action
of formaldehyde on the complex) with mixed aldehydes. Reacting the triimine
derivative of sen L17 with ethanal result in a cryptand with a methanal
pendant on the apical carbon of the new cap L83. If one of the imine groups is
removed to leave the diimine derivative of sen as the precursor complex this
may be reacted with a functionalised ethanal ( RCH2CHO, R= H, Me, Ph). An
intermediate such as L84 results from the reaction of the two acidic protons of
the methylene and subsequent intramolecular condensation produces a
monoimine with a standard size 'cap'. When reduction with NaBH4 follows,
this results in the R-group being the apical pendant to the new cap, as in the
cryptand L85. Throughout this chemistry the cobalt ion remains trapped in the
macrobicycle.
31
Another variation based on [Co(L17)]3+ is to react it with formaldehyde and
either AsH360 or PH3
61 in the presence of base. This results in a capped
macrobicycle with either an arsenic L86 or a phosphorous L87 atom occupying
the apex of the new cap in a form similar to the reaction between [Co(L17)]3+,
formaldehyde and ammonia. The products L86 and L87 analogues of L18, but
the reactions are performed under more stringently controlled conditions.
32
1.5 Reactions Involving Formaldehyde and Bifunctional
Methylene Compounds
The acidity of methylene compounds can be enhanced by having two
electron-withdrawing groups bound directly to the active methylene, i.e.
X-CH2-Y molecules. Examples of molecules in this category include
diethyl malonate (EtOOC-CH2-COOEt) and related molecules such as NC-
CH2-COOEt and EtOOC-CH2-NO2. Clearly, the two acidic protons of the
methylene can be employed in condensation reactions, leading to
molecules with two pendants carrying additional functionality, although
there is the prospect of these being involved in additional or alternate
reactions in some cases, as addressed below.
1.5.1 Diethyl Malonate
Diethyl malonate exhibits sufficent acidity , as a result of the two ester
groups, to function as a relatively strong carbon acid. The two methylene
protons can participate in condenstion reactions with two formaldehyde
molecules and two adjacent coordinated amines in the presence of base,
generating a new six membered chelate ring with a -NH-CH2-C(COOEt)2-
CH2-NH- bridge. This is essentially the same behaviour exhibited by
nitroethane. The resultant gem diester is susceptible to both ester
hydrolysis and decarboxylation, leading eventually to a free acid pendant,
possibly by the route in eq. (8).
33
Where three coordinated amines are available on an octahedral face, the
ester groups in diethyl malonate can be involved in a condensation
reaction in addition to the two acidic methylene protons. Following
condensation with two primary coordinated amines and two formaldehyde
molecules, an intermediate with an ester group and a coordinated primary
amine adjacent is formed (eq. 9, centre) which in basic conditions can
condense further to produce a coordinate amide and complete the 'cap'.
This latter reaction has not been observed as an alternative path in eq. (8),
implying that reaction as a carbon acid is more facile.
34
Reactions with labile metal ions such as copper(II) or nickel(II), where
square planarity is preferred, have been examined in some detail. The
higher pKa of the acidic protons in diethyl malonate in comparison to those
of nitroethane means that reactions involving these reagents do not tend
to proceed as easily as those using nitroethane under identical conditions.
Depending upon the conditions of the reaction, the diester may hydrolyse
and/or decarboxylate to form a mixture of acid ester and monoester
products (eq. 8).
The tetramethyl ester cyclam analogue L88 has been prepared using
dimethylmalonate and formaldehyde (diethylmalonate is equally effective)
in a procedure analogous to that used to produce L4562. Both copper(II)
and nickel(II) templates have been used, as well as the alternative carbon
acid diethylmalonate (which produces the tetraethyl ester). In all
instances, however, the yield tends to be low (ca. 10%), with base induced
decomposition of the precursor complex taking place in competition under
the conditions employed. The analogous procedure has also been carried
out on optically active [Cu(chxn)2]2+ using diethylmalonate to produce the
tetraester L89.45
However, the half capped analogue produced by the controlled addition of
diethylmalonate and formaldehyde to a basic methanolic suspension of
bis(ethane-1,2-diamine)copper(II) perchlorate proceeds readily in good
yield (at least 40%)63. The final product L90 has one acid pendant and one
35
ethyl ester pendant group as opposed to the retention of all the ester
groups in the synthesis of the macrocyclic analogue. It is readily
decarboxylated to the monoacid L92. Apart from reactions involving
ethane-1,2-diamine, the basic synthetic method has been applied to a large
variety of polyamines to produce a number of cyclic and acyclic species, all
with either acid or ester pendant groups (L92, L93, L9464, L9565, L9666,
L9745).
Another variation is the use of diethylmalonate and nitroethane
condensation in the same molecule. In a multiple step process commencing
with [Cu(en)2]2+, capping using diethylmalonate was employed to produce
L90. This species is then stabilised by conversion to the methyl ester
36
derivative of L91 by hydrolysis in basic methanol. The other pair of
primary amines of the intermediate complex molecule is then capped
using nitroethane, the methyl ester being hydrolyzed in the process. The
resulting complex L109AA is a cyclam derivative with both nitro and
carboxylate pendant group which, after reduction to convert the nitro to
an amine and to remove the metal, is capable of encapsulating a wide
range of octahedral metal ions as a sexidentate ligand L99.67 Also
produced from this reaction is the analogous cis isomer in proportions
similar to that found for the L45, L46.
Likewise, L88 can be converted by hydrolysis and decarboxylation
reactions to the potentially sexidentate ligand L100 (L89 can also undergo
the analogous process to produce diacid species). Although no cis/trans
isomerisation is possible for the tetraester, the hydrolysis and
37
decarboxylation reactions produces both isomers, with a strong preference
for the trans form (4:1, as is discussed in later chapters). Since L45 can be
readily reduced to the hexamine L101, the three ligands L99L101 (and
there cis analogues) represent a series of potentially sexidentate
macrocyclic tetraamines with two pendant donors, where the pendant
donors step from two amines, to an amine and a carboxylate, to two
carboxylates. The coordination chemistry and synthesis L99 and L100 are
discussed in detail in Chapters 4 and 5 and compared with the well
characterised complexes of L101.
Reaction of inert hexaamine cobalt(III) complexes with formaldehyde and
diethylmalonate have been described only recently. Reaction of Co(en)33+
generates essentially only the mono-capped molecule L102, capping at the
other face of primary amines not being observed. However, commencing
with Co(L17)3+ or Co(L24)3+ yields macrobicyclic amides L103 and L104
respectively. The pendant ester group can be converted via standard
organic chemistry reactions to the acid (via base hydrolysis) and the acid
chloride (via reaction with thionyl chloride), the later then capable of facile
condensation reaction with amines. The half-capped cobalt(III) complex of
L102 can be converted by reaction with formaldehyde and nitroethane to
L105. The coordinated amide is extraordinarily robust, being unaffected
by these reactions, but is also not conveniently reduced.
38
1.5.2 Other Reagents
There are a number of other conveniently available bifunctional
methylene compounds which are sufficiently strong carbon acids to permit
participation in reactions analogous to those described above. The
'composite' molecule EtOOC-CH2-NO2 is a clear candidate, but few
reactions with the molecule have been reported to date, beyond some
evidence for the formation of L10668 in a condensation reaction with
formaldehyde and a tetraamine copper(II) ion.
39
Bifunctional methylene compounds incorporating nitriles are candidates
for condensations, and some examination of NC-CH2-COOEt and NC-CH2-
CN has been performed. The latter appears to yield L107 in condensation
reactions analogous to L45, but the stability of the pendant molecule is not
apparently great and the product has not been definitely confirmed. The
former reagent undergoes an analogous reaction to form L108.45 The
former reagent also undergoes an analogous reaction to diethyl malonate
with Co(L17)3+ to produce L109. In principle, provided acidity is great
enough, reactions should proceed essentially as defined for diethyl
malonate, although the possible diversion of the reaction along alternative
paths is not well understood, and offers avenues for further examination.
40
1.6 Conclusions
The synthesis of macrocycles, particularly saturated macromonocycles and
macrobicycles incorporating mainly nitrogen donors, is often facile when
inert or highly stable labile complexes with appropriately disposed
coordinated primary amines are reacted with formaldehyde and ammonia
or functionalised methylene compounds which are efficient carbon acids.
Around inert octahedral metal ions, saturated and usually macrobicylcic
molecules are readily accessible. Around more labile metal ions, such as
copper(II), nickel(II) and palladium(II), there is a tendency to form usually
saturated macromonocyclic molecules, directed by a preference for four-
coordination and square planarity with strong-field ligands in those cases.
In many cases, the resultant ligand can be removed from the metal ion in
an intact or slightly amended form. For example, copper(II) complexes of
macrocycles produced from reactions described above may often be
obtained simply by a zinc/acid reduction reaction with following
chromatography on Dowex resin to isolate the metal-free pendant-arm
macrocycle in high yield.69 Where inert complexes such as cobalt(III)
complexes of macrobicycles are produced, the metal-free macrobicyclic
ligand may be obtained by reaction under an oxygen-free atmosphere of
the reduced cobalt(II) complex either with concentrated hydrobromic acid
41
or with excess cyanide ion, which remove the cobalt(II) as CoBr42- or
Co(CN)42- respectively.70
The capacity of the pendant-arm macromonocycles and macrobicycles to
bind metal ions strongly and in some cases selectively, and the unusual
physical properties often shown by complexes of these isolated ligands,
provides a wealth of additional chemistry which is still under active
investigation. In the following chapters, the synthesis and coordination
chemistry of a number of the macromonocycles bearing pendant
carboxylates discussed is described and compared with the already
extensive information concerning their amine pendant analogues.
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